This invention relates to 5-aryl-2,4-dialkyl-3H-1,2,4-triazole-3-thiones, to the intermediates and processes for their preparation, to their pharmacological properties, and to their use as antidepressants.
More specifically, this invention relates to compounds of the formula ##STR1## and the tautomers thereof, wherein R represents halogeno, C.sub.1-6 lower alkyl, C.sub.1-6 lower alkoxy, hydroxy, methylenedioxy or trifluoromethyl with n being 1 or 2, and each of R.sub.2 and R.sub.4 independently represent C.sub.1-6 lower alkyl.
Preferably halogeno represents chloro or fluoro, and methyl and ethyl represent the preferred lower alkyl moieties, although all the straight, branched and cyclic manifestations thereof such as n-propyl, cyclopentyl, cyclohexyl and cyclopropyl are herein included. Lower alkoxy radicals includes ethers having alkyl moieties paralleling the C.sub.1-6 alkyl group. Preferably n is one representing a mono-substituted phenyl moiety with the R-substituted being a group located at any of the ortho, meta or para positions, although the para-substituted compounds are preferred. When di-substituted (i.e., n is 2), the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5- positions are contemplated. The tautomeric forms are included for each of the compounds embraced within formula I. Preferably R.sub.2 and R.sub.4 each represent an alkyl group, especially methyl or ethyl.
The compounds of formula I may readily be prepared using processes and procedures analogously known in the art as seen by the following reaction scheme. ##STR2## wherein R.sub.2, R.sub.4, R.sub.n are as defined above and represents phenyl.
In step A, the preparation of the thiosemicarbazides (IV) is readily effected by reacting a hydrazine (II) with an isothiocyanate (III) by contacting the reactants in a suitable solvent. The reaction is quite rapid and may be carried out at 0.degree. C. to room temperature. Although the reaction proceeds rapidly, the mixture may be left for up to 24 hours without significant decrease in yields. Reflux conditions may be employed but are not preferred. Almost all solvents (with the exception of water and organic acids) may be used. Anhydrous alcohols (preferably ethanol or methanol) are preferred although DMF, CHCl.sub.3, CH.sub.2 Cl.sub.2, THF and Et.sub.2 O may also be used. The required hydrazines and isothiocyanates are readily available but may be prepared by known techniques quite obvious to one of ordinary skill in the art.
In Step B, the desired benzoyl-substituted thiosemicarbazides (VI) may be prepared by reacting the thiosemicarbazides (IV) with an R-substituted-benzoyl chloride (V) in an aprotic solvent such as pyridine, CHCl.sub.3, THF and the like. The acylation proceeds rather easily at temperatures ranging from 0.degree. C. to room temperature over periods of 3 to 24 hours although elevated temperatures (e.g. reflux temperatures) may be employed. Again, the acid halides (V) generally are commercially available but may also be prepared from the corresponding acids which are available from obvious starting materials.
In Step C, the benzoyl thiosemicarbazides (VI) are subjected to a cyclization reaction which is effected by heating the compounds (VI) in an aqueous base, preferably using 1 molar equivalent of the base (e.g. sodium bicarbonate or sodium hydroxide). Alcoholic bases may be utilized but generally are less desirable. The reaction is conducted at about the reflux temperature of the solvent, preferably at about 65.degree.-100.degree. C. In practice, the thiosemicarbazides (VI) need not be purified for use in Step C so that even 1:1 mixtures with pyridine hydrochloride may be used.